title: Tacrolimus exposure and mycophenolate pharmacokinetics and pharmacodynamics early after liver transplantation.
abstract: BACKGROUND
  Mycophenolic acid (MPA) and tacrolimus play important roles in immunosuppressive therapy after solid organ transplantation (Tx) and show large intra- and interindividual pharmacokinetic (PK) variabilities. The purpose of this study was to describe the intra- and interindividual variabilities of MPA and tacrolimus PKs during the first 3 weeks after adult liver transplantation. Furthermore, inosine monophosphate dehydrogenase activity was investigated.
  
  
  METHODS
  This study describes PK and pharmacodynamic parameters of MPA and the PKs of tacrolimus in 16 liver transplant recipients, in 4 follow-up periods (I-IV).
  
  
  RESULTS
  The area under the concentration-time curve (AUC(0-12 hours)) for tacrolimus was low early after Tx (eg, median 78.6 around day 4) and variable in all 4 periods ranging from 3.8 to 267 μg h/L, whereas the predose concentrations (C₀) were 0.0-17.9 μg/L. From periods I to IV, the tacrolimus dose was doubled and the median dose per body weight-adjusted AUC(0-12 hours) increased by 123% (P = 0.017). The AUC(0-12 hours) of MPA was in the range 8.6-57.4 mg h/L, with median values from 21.9 to 27.8 mg h/L, whereas C₀ was between 0.0 and 7.3 mg/L in the 4 periods (medians from 1.2 to 1.6 mg/L). The maximum inhibition of inosine monophosphate dehydrogenase within a dose interval ranged from 9.5% to 100%.
  
  
  CONCLUSIONS
  This study confirmed the large variability in the PKs of tacrolimus and MPA in liver transplant recipients. In particular, the MPA AUC(0-12 hours) was consistently low in all 4 periods. We also observed a low tacrolimus exposure during the first days after transplant compared with the following weeks.
authors.affiliation: *Department of Medical Biochemistry, Oslo University Hospital; †Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo; Departments of ‡Transplantation Medicine; and §Pharmacology, Oslo University Hospital, Oslo, Norway.
authors.forename: Ingjerd
authors.initials: I
authors.lastname: Sæves
authors.forename: Pål-Dag
authors.initials: PD
authors.lastname: Line
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.forename: Nils T
authors.initials: NT
authors.lastname: Vethe
authors.forename: Ragnhild G
authors.initials: RG
authors.lastname: Tveit
authors.forename: Tore J
authors.initials: TJ
authors.lastname: Meltevik
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D016559:Tacrolimus